Purpose: We investigated serotonergic and dopaminergic terminal integrity role in PRKN-associated Parkinsonism (PRKN-PD) using [¹¹C]DASB Positron Emission Tomography (PET) and [¹²³I]FP-CIT Single Photon Emission Computerised Tomography (SPECT).

Methods: Fourteen PRKN-PD patients (mean age 49.70 ± 10.83, disease duration 10.95 ± 7.59 years, H&Y 2.0 ± 0.68), and twelve iPD patients (mean age 65.40 ± 7.48 years, disease duration 5.05 ± 4.50 years, H&Y 2.0 ± 0.93) underwent clinical assessments, 3-Tesla MRI, [¹¹C]DASB PET-CT, and [¹²³I]FP-CIT SPECT, and compared with previously acquired healthy control (HCs) data. [¹¹C]DASB distribution volume ratio (DVR) parametric images were generated and DVR-1 values, equivalent to BPND, sampled from a priori selected regions-of-interest (ROIs) with the posterior cerebellum as reference. [¹²³I]FP-CIT images underwent reconstruction and normalization to standard space, and striatal Specific Binding Ratio (SBR) calculated from the eight hottest consecutive slices.

Results: PRKN-PD patients showed 20.8% to 45.2% [¹¹C]DASB BPND loss across several cortical and subcortical ROIs compared to HCs (p ≤ 0.01). After adjusting for age and disease duration, no differences in [¹¹C]DASB BPND were observed between PRKN-PD and iPD. In PRKN-PD, higher [¹¹C]DASB BPND in the raphe, brainstem, ventral striatum, and amygdala, correlated with higher scores on the Non-Motor Symptoms Scale (p < 0.05). Higher [¹¹C]DASB BPND in the caudate and putamen correlated with higher scores on the Beck Depression Inventory II scale (p < 0.05). No correlation was detected between [¹¹C]DASB BPND and [¹²³I]FP-CIT SBR in the caudate and putamen.

Conclusions: PRKN-PD is characterized by widespread serotonergic dysfunction, which is independent of dopaminergic degeneration and linked to key non-motor symptoms, particularly depression. These findings provide novel insights into the pathophysiology of PRKN-PD.